The Baltimore Longitudinal Study of Aging (BLSA) prostate aging and disease study has both retrospective and prospective arms involving repeated assessments of anatomical, physiological, hormonal, and behavioral aspects of age-associated changes in prostate size. The retrospective arm of the study examines the sex steroid and PSA levels from frozen sera stored during the three most recent visits and visits closest to 10, 15, 20 and 25 years before study initiation. The prospective arm involves male BLSA participants and has continued for more than 15 years. Data collection was on hold starting in December 2002, and was restarted in approximately August 2005. [unreadable] Our previous work suggests that prostate cancer develops over a period of at least 10 years in most men, and that PSA can stratify men at risk as long as 20 to 30 years prior to prostate cancer diagnosis. These observations argue that there is a long time period in the development of prostate cancer, where preventive strategies might decrease the risk for prostate cancer and perhaps for better identifying men where the prostate cancer might be life threatening. [unreadable] Recent work has focused on identifying men who develop life threatening prostate cancer that can be detected during clinical evaluation at a time when the cancer should be curable. A major concern with the use of PSA for early diagnosis, or as a risk factor for future prostate cancer diagnosis is the likelihood that the identified cancer will be low grade and would never threaten the well-being or life of the individual man. We have found that PSA velocity had a relative risk for having a life-threatening prostate cancer of approximately 4.0 (1.2-12.9) per ng/ml/yr increase and that these effects were present 10-15 years prior to prostate cancer diagnosis. These observations suggest that at a time when PSA levels indicate the presence of curable prostate cancer, PSA velocity may help identify men with life threatening disease.[unreadable] Recently, we have extended this concept by asking whether using a mans cumulative PSA history can improve the assessment of future risk of having a life-threatening prostate cancer. Using a simple additive approach where at each evaluation the health care provider sums the number of PSA evaluations where the patient has met a simple rule, the probability of having or developing a life threatening prostate cancer can be estimated. For example, a man over the age of 40 who never meets the rule of having a PSA velocity greater than 0.2 mg/year, will have less than a 2-4% probability of developing a life-threatening prostate cancer, while a man who has met this rule on 5 consecutive yearly evaluations has a risk of 19% (CI=8-35%), despite the likelihood that his PSA is still quite normal. [unreadable] Whether the use of PSA velocity is the most useful approach to describe change in PSA over time has been argued. Some researchers believe that using the time it takes for the PSA level to double is actually more appropriate. Less is known about the relative utility of PSA doubling time to predict tumor aggressiveness. We have examined this question, and found that within the period of 5 yr prior to diagnosis, PSA velocity but not doubling time was associated with high-risk or fatal disease. These data suggest that PSA velocity appears to be more useful than doubling time in identifying those men with life- threatening disease.[unreadable] Another concern in relationship to prostate cancer is whether screening is appropriate and for which men and at what age. There is currently no general agreement on who should be screened and when. Little work has been directed at the question of when to stop screening if it is being done. We have addressed this question in relationship to the identification of life- threatening prostate cancer. In our analyses, we find that men older than 75 years with a PSA less than 3 ng/ml have essentially zero risk of subsequently developing a life threatening prostate cancer. Thus, stopping PSA testing in the presence of low measurements is a low risk procedure in this older age group. [unreadable] A second area of interest is benign prostatic hyperplasia (BPH) which is a common problem affecting more than 90% of men by the age of 80 years. The causes of growth in the gland are multifactorial and is directly related to androgenic hormones. BPH is a major health problem requiring treatment in more than 25% of men. We have been interested in the natural history of prostate growth, and in understanding the association between aging, prostate growth and the development of BPH and symptoms. Although prostate specific antigen velocity was proposed to increase the specificity of prostate specific antigen based screening, there is little information on the effect of differential prostate growth on prostate specific antigen velocity. In 242 men without prostate cancer who had 2 or more serial pelvic magnetic resonance imaging studies and contemporaneous prostate specific antigen measurements over a median of 4.2 years of followup, no correlation was found between the median rate of prostate volume change (0.6 cc per year) and the median prostate specific antigen change (0.03 ng/ml per year). Our data suggest that volume increases alone do not cause a high prostate specific antigen velocity. Despite growth rates as high as 10 cc per year, prostate specific antigen velocity was less than 0.1 ng/ml per year in most men without prostate cancer. Thus, differential rates of prostatic growth should not confound the use of prostate specific antigen velocity for prostate cancer detection and prognostication.[unreadable] At this time, we are continuing to examine factors that contribute to prostate growth and the development of cancer, and strategies for early diagnosis of prostate disease with a focus on the identification of risk for high risk cancers. In the coming year, we are planning an examination of a new marker for prostate cancer, and to begin a study of the genetic characteristics for the development of high risk prostate cancer.